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Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response

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Abstract

Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs). Recent reports indicate that the UPRs may play an important role in immune responses. Notably, the homeostasis-regulating hormones oxytocin (OXT) and vasopressin (AVP) are also associated with the regulation of inflammatory responses and immune function. Intriguingly, OXT and AVP have been linked with ER unfolded protein responses (UPRER), and can impact ROS production and mitochondrial function. Here, we will review the evidence for interactions between these various factors and how these neuropeptides might influence mitochondrial processes.

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References

  • Acher R, Chauvet J, Chauvet MT (1995) Man and the chimaera. Selective versus neutral oxytocin evolution. Adv Exp Med Biol 395:615–627

    CAS  PubMed  Google Scholar 

  • Akman T, Akman L, Erbas O et al (2015) The preventive effect of oxytocin to cisplatin-induced neurotoxicity: an experimental rat model. Biomed Res Int 2015:167235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alberi S, Dreifuss JJ, Raggenbass M (1997) The oxytocin-induced inward current in vagal neurons of the rat is mediated by G protein activation but not by an increase in the intracellular calcium concentration. Eur J Neurosci 9:2605–2612

    Article  CAS  PubMed  Google Scholar 

  • Ameri K, Harris AL (2008) Activating transcription factor 4. Int J Biochem Cell Biol 40:14–21

    Article  CAS  PubMed  Google Scholar 

  • Amini-Khoei H, Mohammadi-Asl A, Amiri S et al (2017) Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation. Prog Neuro-Psychopharmacol Biol Psychiatry 76:169–178

    Article  CAS  Google Scholar 

  • Asada R, Kanemoto S, Kondo S et al (2011) The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J Biochem 149:507–518

    Article  CAS  PubMed  Google Scholar 

  • Azuma Y, Hagiwara D, Lu W et al (2014) Activating transcription factor 6α is required for the vasopressin neuron system to maintain water balance under dehydration in male mice. Endocrinology 155:4905–4914

    Article  CAS  PubMed  Google Scholar 

  • Baker BM, Nargund AM, Sun T, Haynes CM (2012) Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2. PLoS Genet 8:e1002760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barreca T, Gandolfo C, Corsini G et al (2001) Evaluation of the secretory pattern of plasma arginine vasopressin in stroke patients. Cerebrovasc Dis 11:113–118

    Article  CAS  PubMed  Google Scholar 

  • Belin V, Moos F, Richard P (1984) Synchronization of oxytocin cells in the hypothalamic paraventricular and supraoptic nuclei in suckled rats: direct proof with paired extracellular recordings. Exp Brain Res 57:201–203

    Article  CAS  PubMed  Google Scholar 

  • Bemana I, Nagao S (1999) Treatment of brain edema with a nonpeptide arginine vasopressin V1 receptor antagonist OPC-21268 in rats. Neurosurgery 44:148–54; discussion 154–5

  • Bénard G, Massa F, Puente N et al (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15:558–564

    Article  CAS  PubMed  Google Scholar 

  • Biyikli NK, Tuğtepe H, Sener G et al (2006) Oxytocin alleviates oxidative renal injury in pyelonephritic rats via a neutrophil-dependent mechanism. Peptides 27:2249–2257

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Hong J-S (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  CAS  PubMed  Google Scholar 

  • Boone M, Deen PMT (2008) Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch 456:1005–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bordt EA, Polster BM (2014) NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radic Biol Med 76:34–46

    Article  CAS  PubMed  Google Scholar 

  • Bourque CW (2008) Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 9:519–531

    Article  CAS  PubMed  Google Scholar 

  • Brownstein MJ, Russell JT, Gainer H (1980) Synthesis, transport, and release of posterior pituitary hormones. Science 207:373–378

    Article  CAS  PubMed  Google Scholar 

  • Casas F, Domenjoud L, Rochard P et al (2000) A 45 kDa protein related to PPARgamma2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett 478:4–8

    Article  CAS  PubMed  Google Scholar 

  • Castoldi A, Naffah de Souza C, Câmara NOS, Moraes-Vieira PM (2015) The macrophage switch in obesity development. Front Immunol 6:637

    PubMed  Google Scholar 

  • Ceanga M, Spataru A, Zagrean A-M (2010) Oxytocin is neuroprotective against oxygen-glucose deprivation and reoxygenation in immature hippocampal cultures. Neurosci Lett 477:15–18

    Article  CAS  PubMed  Google Scholar 

  • Celli J, Tsolis RM (2015) Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? Nat Rev Microbiol 13:71–82

    Article  CAS  PubMed  Google Scholar 

  • Cetinel S, Hancioğlu S, Sener E et al (2010) Oxytocin treatment alleviates stress-aggravated colitis by a receptor-dependent mechanism. Regul Pept 160:146–152

    Article  CAS  PubMed  Google Scholar 

  • Chakravarthi S, Jessop CE, Bulleid NJ (2006) The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress. EMBO Rep 7:271–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaves VE, Tilelli CQ, Brito NA, Brito MN (2013) Role of oxytocin in energy metabolism. Peptides 45:9–14

    Article  CAS  PubMed  Google Scholar 

  • Chen JQ, Delannoy M, Cooke C, Yager JD (2004) Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. Am J Physiol Endocrinol Metab 286:E1011–E1022

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Hallenbeck JM, Ruetzler C et al (2003) Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab 23:748–755

    Article  CAS  PubMed  Google Scholar 

  • Collins LV, Hajizadeh S, Holme E et al (2004) Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol 75:995–1000

    Article  CAS  PubMed  Google Scholar 

  • Crambert G, Ernandez T, Lamouroux C, et al (2014) Epithelial sodium channel abundance is decreased by an unfolded protein response induced by hyperosmolality. Physiol Rep 2. https://doi.org/10.14814/phy2.12169

  • Das B, Sarkar C (2012) Is preconditioning by oxytocin administration mediated by iNOS and/or mitochondrial K(ATP) channel activation in the in vivo anesthetized rabbit heart? Life Sci 90:763–769

    Article  CAS  PubMed  Google Scholar 

  • Declercq ER, Sakala C, Corry MP et al (2014) Major survey findings of listening to mothers(SM) III: pregnancy and birth: report of the third national U.S. survey of women’s childbearing experiences. J Perinat Educ 23:9–16

    Article  PubMed  PubMed Central  Google Scholar 

  • Diano S, Urbanski HF, Horvath B et al (2000) Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology 141:4226–4238

    Article  CAS  PubMed  Google Scholar 

  • Di Benedetto A, Sun L, Zambonin CG et al (2014) Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor. Proc Natl Acad Sci U S A 111:16502–16507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dickinson LD, Betz LA (2016) Attenuated Development of Ischemic Brain Edema in Vasopressin-Deficient Rats. Journal of Cerebral Blood Flow & Metabolism 12 (4):681–690

  • Du D, Jiang M, Liu M et al (2015) Microglial P2X7 receptor in the hypothalamic paraventricular nuclei contributes to sympathoexcitatory responses in acute myocardial infarction rat. Neurosci Lett 587:22–28

    Article  CAS  PubMed  Google Scholar 

  • Dumais KM, Veenema AH (2016) Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 40:1–23

    Article  CAS  PubMed  Google Scholar 

  • Echtay KS (2007) Mitochondrial uncoupling proteins—what is their physiological role? Free Radic Biol Med 43:1351–1371

    Article  CAS  PubMed  Google Scholar 

  • Ficek W (1983) Physiological dependency between the hypothalamus and the thymus of Wistar rats. IV. Organotypic culture of the thymus in the presence of hypophyseal hormones, vasopressin, and oxytocin. Gegenbaurs Morphol Jahrb 129:445–458

    CAS  PubMed  Google Scholar 

  • Fiorese CJ, Schulz AM, Lin Y-F et al (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol 26:2037–2043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frantz S, Nahrendorf M (2014) Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res 102:240–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuchs AR, Poblete VF Jr (1970) Oxytocin and uterine function in pregnant and parturient rats. Biol Reprod 2:387–400

    Article  CAS  PubMed  Google Scholar 

  • Gargalovic PS, Gharavi NM, Clark MJ et al (2006) The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 26:2490–2496

    Article  CAS  PubMed  Google Scholar 

  • Ghiringhelli F, Apetoh L, Tesniere A et al (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15:1170–1178

    Article  CAS  PubMed  Google Scholar 

  • Gillies GE, Linton EA, Lowry PJ (1982) Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299:355–357

    Article  CAS  PubMed  Google Scholar 

  • Gkogkas CG, Khoutorsky A, Ran I et al (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371–377

    Article  CAS  PubMed  Google Scholar 

  • Gobrogge K, Wang Z (2015) Neuropeptidergic regulation of pair-bonding and stress buffering: lessons from voles. Horm Behav 76:91–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodson JL (2008) Nonapeptides and the evolutionary patterning of sociality. Prog Brain Res 170:3–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gravina FS, Jobling P, Kerr KP et al (2011) Oxytocin depolarizes mitochondria in isolated myometrial cells. Exp Physiol 96:949–956

    Article  CAS  PubMed  Google Scholar 

  • Greenwood M, Bordieri L, Greenwood MP et al (2014) Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus. J Neurosci 34:3810–3820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwood M, Greenwood MP, Paton JFR, Murphy D (2015a) Transcription factor CREB3L1 regulates endoplasmic reticulum stress response genes in the osmotically challenged rat hypothalamus. PLoS One 10:e0124956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwood MP, Mecawi AS, Hoe SZ et al (2015b) A comparison of physiological and transcriptome responses to water deprivation and salt loading in the rat supraoptic nucleus. Am J Phys Regul Integr Comp Phys 308:R559–R568

    CAS  Google Scholar 

  • Haddad JJ, Land SC (2002) Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. Br J Pharmacol 135:520–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagiwara D, Arima H, Morishita Y et al (2012) BiP mRNA expression is upregulated by dehydration in vasopressin neurons in the hypothalamus in mice. Peptides 33:346–350

    Article  CAS  PubMed  Google Scholar 

  • Hagiwara D, Arima H, Morishita Y et al (2014) Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus. Cell Death Dis 5:e1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamilton BE, Martin JA, Osterman MJK et al (2015) Births: final data for 2014. Natl Vital Stat Rep 64:1–64

    PubMed  Google Scholar 

  • Harding HP, Novoa I, Zhang Y et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  CAS  PubMed  Google Scholar 

  • Harkany T, Horvath TL (2017) (S)pot on mitochondria: cannabinoids disrupt cellular respiration to limit neuronal activity. Cell Metab 25:8–10

    Article  CAS  PubMed  Google Scholar 

  • Haschemi A, Kosma P, Gille L et al (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15:813–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Havránek T, Lešťanová Z, Mravec B et al (2017) Oxytocin modulates expression of neuron and glial markers in the rat hippocampus. Folia Biol 63:91–97

    Google Scholar 

  • Haynes CM, Yang Y, Blais SP et al (2010) The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol Cell 37:529–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haze K, Yoshida H, Yanagi H et al (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hebert-Chatelain E, Desprez T, Serrat R et al (2016) A cannabinoid link between mitochondria and memory. Nature 539:555–559

    Article  CAS  PubMed  Google Scholar 

  • Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102

    Article  CAS  PubMed  Google Scholar 

  • Hetz C, Martinon F, Rodriguez D, Glimcher LH (2011) The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiol Rev 91:1219–1243

    Article  CAS  PubMed  Google Scholar 

  • Honma Y, Kanazawa K, Mori T et al (1999) Identification of a novel gene, OASIS, which encodes for a putative CREB/ATF family transcription factor in the long-term cultured astrocytes and gliotic tissue. Brain Res Mol Brain Res 69:93–103

    Article  CAS  PubMed  Google Scholar 

  • Horvath TL, Warden CH, Hajos M et al (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19:10417–10427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou D, Jin F (2016) Model roles of the hypothalamo-neurohypophysial system in neuroscience study. Biochem Pharmacol 5: https://doi.org/10.4172/2167-0501.1000211

  • Işeri SO, Sener G, Sağlam B et al (2005) Oxytocin ameliorates oxidative colonic inflammation by a neutrophil-dependent mechanism. Peptides 26:483–491

    Article  CAS  PubMed  Google Scholar 

  • Iyer SS, He Q, Janczy JR et al (2013) Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39:311–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer SS, Pulskens WP, Sadler JJ et al (2009) Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A 106:20388–20393

    Article  PubMed  PubMed Central  Google Scholar 

  • Jaber SM, Bordt EA, Bhatt NM, et al (2017) Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension. Neurochem Int https://doi.org/10.1016/j.neuint.2017.09.003

  • Jankowski M, Bissonauth V, Gao L et al (2010) Anti-inflammatory effect of oxytocin in rat myocardial infarction. Basic Res Cardiol 105:205–218

    Article  CAS  PubMed  Google Scholar 

  • Jeong D-E, Lee D, Hwang S-Y et al (2017) Mitochondrial chaperone HSP-60 regulates anti-bacterial immunity via p38 MAP kinase signaling. EMBO J 36:1046–1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jha AK, Huang SC-C, Sergushichev A et al (2015) Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42:419–430

    Article  CAS  PubMed  Google Scholar 

  • Kaneko Y, Pappas C, Tajiri N, Borlongan CV (2016) Oxytocin modulates GABAAR subunits to confer neuroprotection in stroke in vitro. Sci Rep 6:35659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang S-W, Rane NS, Kim SJ et al (2006) Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell 127:999–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karelina K, Stuller KA, Jarrett B et al (2011) Oxytocin mediates social neuroprotection after cerebral ischemia. Stroke 42:3606–3611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khazipov R, Tyzio R, Ben-Ari Y (2008) Effects of oxytocin on GABA signalling in the foetal brain during delivery. Prog Brain Res 170:243–257

  • Kelleher RJ 3rd, Bear MF (2008) The autistic neuron: troubled translation? Cell 135:401–406

    Article  CAS  PubMed  Google Scholar 

  • Kelly AM, Goodson JL (2014) Social functions of individual vasopressin-oxytocin cell groups in vertebrates: what do we really know? Front Neuroendocrinol 35:512–529

    Article  CAS  PubMed  Google Scholar 

  • Klein BY, Tamir H, Hirschberg DL et al (2013) Oxytocin modulates mTORC1 pathway in the gut. Biochem Biophys Res Commun 432:466–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein BY, Tamir H, Hirschberg DL et al (2014) Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells. Cell Stress Chaperones 19:465–477

    Article  CAS  PubMed  Google Scholar 

  • Klein BY, Tamir H, Hirschberg DL et al (2016) Oxytocin opposes effects of bacterial endotoxin on ER-stress signaling in Caco2BB gut cells. Biochim Biophys Acta 1860:402–411

    Article  CAS  PubMed  Google Scholar 

  • Knupp J, Arvan P, Chang A (2018) Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress. Cell Death Differ https://doi.org/10.1038/s41418-018-0133-4

  • Kohr MJ, Sun J, Aponte A et al (2011) Simultaneous measurement of protein oxidation and S-nitrosylation during preconditioning and ischemia/reperfusion injury with resin-assisted capture. Circ Res 108:418–426

    Article  CAS  PubMed  Google Scholar 

  • Kondo S, Saito A, Asada R et al (2011) Physiological unfolded protein response regulated by OASIS family members, transmembrane bZIP transcription factors. IUBMB Life 63:233–239

    Article  CAS  PubMed  Google Scholar 

  • Kotas ME, Medzhitov R (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozniewska E, Romaniuk K (2008) Vasopressin in vascular regulation and water homeostasis in the brain. J Physiol Pharmacol 59(Suppl 8):109–116

    PubMed  Google Scholar 

  • Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krysko DV, Agostinis P, Krysko O et al (2011) Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32:157–164

    Article  CAS  PubMed  Google Scholar 

  • Lampropoulou V, Sergushichev A, Bambouskova M et al (2016) Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24:158–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25:150–176

    Article  CAS  PubMed  Google Scholar 

  • Lee A-H, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Sharma S, Kim J et al (2008) Mitochondrial nuclear receptors and transcription factors: who’s minding the cell? J Neurosci Res 86:961–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee K, Tirasophon W, Shen X et al (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16:452–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehninger AL, Neubert D (1961) Effect of oxytocin, vasopressin, and other disulfide hormones on uptake and extrusion of water by mitochondria. Proc Natl Acad Sci U S A 47:1929–1936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit Cancer cells? Trends Biochem Sci 41:211–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T, Wang P, Wang SC, Wang Y-F (2016) Approaches mediating oxytocin regulation of the immune system. Front Immunol 7:693

    PubMed  Google Scholar 

  • Lipton P (1999) Ischemic Cell Death in Brain Neurons. Physiological Reviews 79(4):1431–1568

  • Liu Y, Samuel BS, Breen PC, Ruvkun G (2014) Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508:406–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7:126–136

    Article  CAS  PubMed  Google Scholar 

  • Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15

    Article  CAS  PubMed  Google Scholar 

  • Martinon F, Chen X, Lee A-H, Glimcher LH (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11:411–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinus RD, Garth GP, Webster TL et al (1996) Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem 240:98–103

    Article  CAS  PubMed  Google Scholar 

  • Masi A, Quintana DS, Glozier N et al (2015) Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 20:440–446

    Article  CAS  PubMed  Google Scholar 

  • Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045

    Article  CAS  PubMed  Google Scholar 

  • McKinley MJ, McAllen RM, Davern P et al (2003) The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol 172:III–XII 1–122, back cover

    CAS  PubMed  Google Scholar 

  • Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435

    Article  CAS  PubMed  Google Scholar 

  • Mehta MM, Weinberg SE, Chandel NS (2017) Mitochondrial control of immunity: beyond ATP. Nat Rev Immunol https://doi.org/10.1038/nri.2017.66

  • Melber A, Haynes CM (2018) UPRmtregulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res 28:281–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michel S, Canonne M, Arnould T, Renard P (2015) Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response. Mitochondrion 21:58–68

    Article  CAS  PubMed  Google Scholar 

  • Michelucci A, Cordes T, Ghelfi J et al (2013) Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A 110:7820–7825

    Article  PubMed  PubMed Central  Google Scholar 

  • Miller DB, O’Callaghan JP (2002) Neuroendocrine aspects of the response to stress. Metabolism 51:5–10

    Article  CAS  PubMed  Google Scholar 

  • Mills EL, Kelly B, Logan A et al (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167:457–470.e13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyazaki S, Hiraoka Y, Hidema S, Nishimori K (2016) Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice. Biochem Biophys Res Commun 472:319–323

    Article  CAS  PubMed  Google Scholar 

  • Morris G, Berk M (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 13:68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami T, Saito A, Hino S-I et al (2009) Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol 11:1205–1211

    Article  CAS  PubMed  Google Scholar 

  • Nakahira K, Haspel JA, Rathinam VAK et al (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230

    Article  CAS  PubMed  Google Scholar 

  • Nargund AM, Fiorese CJ, Pellegrino MW et al (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell 58:123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nargund AM, Pellegrino MW, Fiorese CJ et al (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337:587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navid F, Colbert RA (2017) Causes and consequences of endoplasmic reticulum stress in rheumatic disease. Nat Rev Rheumatol 13:25–40

    Article  CAS  PubMed  Google Scholar 

  • Neubert D, Lehninger AL (1962) The effect of thiols and disulfides on water uptake and extrusion by rat liver mitochondria. J Biol Chem 237:952–958

    CAS  PubMed  Google Scholar 

  • Neves-Pereira M, Müller B, Massie D et al (2009) Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 46:759–765

    Article  CAS  PubMed  Google Scholar 

  • Ocampo Daza D, Lewicka M, Larhammar D (2012) The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, inclucing two distinct V2 subtypes. Gen Comp Endocrinol 175:135–143

    Article  CAS  PubMed  Google Scholar 

  • Oliveira AN, Hood DA (2018) Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPRmt in muscle. Am J Physiol Cell Physiol https://doi.org/10.1152/ajpcell.00275.2017

  • Oliveira-Pelegrin GR, Saia RS, Cárnio EC, Rocha MJA (2013) Oxytocin affects nitric oxide and cytokine production by sepsis-sensitized macrophages. Neuroimmunomodulation 20:65–71

    Article  CAS  PubMed  Google Scholar 

  • Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665

    Article  CAS  PubMed  Google Scholar 

  • Oyadomari S, Yun C, Fisher EA et al (2006) Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell 126:727–739

    Article  CAS  PubMed  Google Scholar 

  • Palmer HJ, Paulson KE (1997) Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr Rev 55:353–361

    Article  CAS  PubMed  Google Scholar 

  • Palsson-McDermott EM, Curtis AM, Goel G et al (2015) Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab 21:65–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pannell M, Szulzewsky F, Matyash V, Wolf SA, Kettenmann H (2014) The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-γ, and IL-4. Glia 62(5):667–679

  • Pearce EJ, Pearce EL (2017) Immunometabolism in 2017: driving immunity: all roads lead to metabolism. Nat Rev Immunol. https://doi.org/10.1038/nri.2017.139

  • Pellegrino MW, Nargund AM, Kirienko NV et al (2014) Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516:414–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pittman QJ, Chen X, Mouihate A et al (1998) Arginine vasopressin, fever and temperature regulation. Prog Brain Res 119:383–392

    Article  CAS  PubMed  Google Scholar 

  • Pittman QJ, Lawrence D, McLean L (1982) Central effects of arginine vasopressin on blood pressure in rats. Endocrinology 110:1058–1060

    Article  CAS  PubMed  Google Scholar 

  • Qin L, Liu Y, Wang T et al (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421

    Article  CAS  PubMed  Google Scholar 

  • Quirós PM, Prado MA, Zamboni N et al (2017) Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol 216:2027–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qureshi MA, Haynes CM, Pellegrino MW (2017) The mitochondrial unfolded protein response: signaling from the powerhouse. J Biol Chem 292:13500–13506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roach JC, Smith KD, Strobe KL et al (2007) Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells. Proc Natl Acad Sci U S A 104:16245–16250

    Article  PubMed  PubMed Central  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  • Rongvaux A (2017) Innate immunity and tolerance toward mitochondria. Mitochondrion https://doi.org/10.1016/j.mito.2017.10.007

  • Roth CL, D’Ambrosio G, Elfers C (2016) Activation of nuclear factor kappa B pathway and reduction of hypothalamic oxytocin following hypothalamic lesions. J Syst Integr Neurosci 2:79–84

    Article  PubMed  PubMed Central  Google Scholar 

  • Runkel ED, Liu S, Baumeister R, Schulze E (2013) Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response. PLoS Genet 9:e1003346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutkowski DT, Hegde RS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189:783–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sagan L (1967) On the origin of mitosing cells. J Theor Biol 14:255–274

    Article  CAS  PubMed  Google Scholar 

  • Schneid-Kofman N, Silberstein T, Saphier O et al (2009) Labor augmentation with oxytocin decreases glutathione level. Obstet Gynecol Int 2009:807659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832

    Article  CAS  PubMed  Google Scholar 

  • Schröder M, Kaufman RJ (2005a) ER stress and the unfolded protein response. Mutat Res 569:29–63

    Article  CAS  PubMed  Google Scholar 

  • Schröder M, Kaufman RJ (2005b) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  CAS  PubMed  Google Scholar 

  • Shao L-W, Niu R, Liu Y (2016) Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res 26:1182–1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimada K, Crother TR, Karlin J et al (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva YJ, Moffat RC, Walt AJ (1969) Vasopressin effect on portal and systemic hemodynamics. Studies in intact, unanesthetized humans. JAMA 210:1065–1068

    Article  CAS  PubMed  Google Scholar 

  • Sims CA, Yuxia G, Singh K et al (2017) Supplemental arginine vasopressin during the resuscitation of severe hemorrhagic shock preserves renal mitochondrial function. PLoS One 12:e0186339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simsek Y, Celik O, Karaer A et al (2012) Elevated cardiac oxidative stress in newborn rats from mothers treated with atosiban. Arch Gynecol Obstet 285:655–661

    Article  CAS  PubMed  Google Scholar 

  • Smith AS, Tabbaa M, Lei K et al (2016) Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrinology 63:50–58

    Article  CAS  PubMed  Google Scholar 

  • Song Z, Albers HE (2017) Cross-talk among oxytocin and arginine-vasopressin receptors: relevance for basic and clinical studies of the brain and periphery. Front Neuroendocrinol. https://doi.org/10.1016/j.yfrne.2017.10.004

  • Sørensen PS, Gjerris A, Hammer M (1985) Cerebrospinal fluid vasopressin in neurological and psychiatric disorders. J Neurol Neurosurg Psychiatry 48:50–57

    Article  PubMed  PubMed Central  Google Scholar 

  • Steen KA, Xu H, Bernlohr DA (2017) FABP4/aP2 regulates macrophage redox signaling and Inflammasome activation via control of UCP2. Mol Cell Biol 37. https://doi.org/10.1128/MCB.00282-16

  • St-Louis R, Parmentier C, Grange-Messent V et al (2014) Reactive oxygen species are physiological mediators of the noradrenergic signaling pathway in the mouse supraoptic nucleus. Free Radic Biol Med 71:231–239

    Article  CAS  PubMed  Google Scholar 

  • St-Louis R, Parmentier C, Raison D et al (2012) Reactive oxygen species are required for the hypothalamic osmoregulatory response. Endocrinology 153:1317–1329

    Article  CAS  PubMed  Google Scholar 

  • Stoop R (2012) Neuromodulation by oxytocin and vasopressin. Neuron 76:142–159

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Steenbergen C, Murphy E (2006) S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal 8:1693–1705

    Article  CAS  PubMed  Google Scholar 

  • Szeto A, Nation DA, Mendez AJ et al (2008) Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. Am J Physiol Endocrinol Metab 295:E1495–E1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szeto A, Sun-Suslow N, Mendez AJ et al (2017) Regulation of the macrophage oxytocin receptor in response to inflammation. Am J Physiol Endocrinol Metab 312:E183–E189

    Article  PubMed  PubMed Central  Google Scholar 

  • Szmydynger-Chodobska J, Fox LM, Lynch KM et al (2010) Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. J Neurotrauma 27:1449–1461

    Article  PubMed  PubMed Central  Google Scholar 

  • Szmydynger-Chodobska J, Zink BJ, Chodobski A (2011) Multiple sites of vasopressin synthesis in the injured brain. J Cereb Blood Flow Metab 31:47–51

    Article  CAS  PubMed  Google Scholar 

  • Ta HM, Le TM, Ishii H et al (2016) Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis. J Neurochem 139:1124–1137

    Article  CAS  PubMed  Google Scholar 

  • Tannahill GM, Curtis AM, Adamik J et al (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trabold R, Krieg S, Schöller K, Plesnila N (2008) Role of Vasopressin V and V Receptors for the Development of Secondary Brain Damage after Traumatic Brain Injury in Mice. Journal of Neurotrauma 25(12):1459–1465

  • Teske BF, Fusakio ME, Zhou D et al (2013) CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis. Mol Biol Cell 24:2477–2490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hubner CA, Represa A, Ben-Ari Y, Khazipov R (2006) Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery. Science 314(5806):1788–1792

  • Vakili A, Kataoka H, Plesnila N (2005) Role of Arginine Vasopressin V and V Receptors for Brain Damage After Transient Focal Cerebral Ischemia. Journal of Cerebral Blood Flow & Metabolism 25(8):1012–1019

  • van Horssen J, van Schaik P, Witte M (2017) Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders? Neurosci Lett https://doi.org/10.1016/j.neulet.2017.06.050

  • Vats D, Mukundan L, Odegaard JI et al (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4:13–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villapol S, Loane DJ, Burns MP (2017) Sexual dimorphism in the inflammatory response to traumatic brain injury. Glia 65:1423–1438

    Article  PubMed  PubMed Central  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Doering LC (2013) Reversing autism by targeting downstream mTOR signaling. Front Cell Neurosci 7:28

    PubMed  PubMed Central  Google Scholar 

  • Wang S, Gao K, Liu Y (2017) UPRmtcoordinates immunity to maintain mitochondrial homeostasis and animal fitness. Mitochondrion https://doi.org/10.1016/j.mito.2017.11.004

  • Wrobel L, Topf U, Bragoszewski P et al (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524:485–488

    Article  CAS  PubMed  Google Scholar 

  • Wrutniak C, Cassar-Malek I, Marchal S et al (1995) A 43-kDa protein related to c-Erb A alpha 1 is located in the mitochondrial matrix of rat liver. J Biol Chem 270:16347–16354

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Hertzel AV, Steen KA et al (2015) Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Mol Cell Biol 35:1055–1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu M, Su W, Huang W-D et al (2007) Effect of AVP on brain edema following traumatic brain injury. Chin J Traumatol 10:90–93

    CAS  PubMed  Google Scholar 

  • Yamamoto K, Sato T, Matsui T et al (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 13:365–376

    Article  CAS  PubMed  Google Scholar 

  • Yoneda T, Benedetti C, Urano F et al (2004) Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci 117:4055–4066

    Article  CAS  PubMed  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A et al (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  CAS  PubMed  Google Scholar 

  • Young WS 3rd, Gainer H (2003) Transgenesis and the study of expression, cellular targeting and function of oxytocin, vasopressin and their receptors. Neuroendocrinology 78:185–203

    Article  CAS  PubMed  Google Scholar 

  • Yuan L, Liu S, Bai X et al (2016) Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. J Neuroinflammation 13:77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng K-W, Zhang T, Fu H et al (2012) Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the toll-like receptor 4-dependent MyD88/IKK/NF-κB signaling pathway in lipopolysaccharide-induced microglia. Eur J Pharmacol 692:29–37

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Raoof M, Chen Y et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng W, Zheng X, Liu S et al (2012) TNFα and IL-1β are mediated by both TLR4 and Nod1 pathways in the cultured HAPI cells stimulated by LPS. Biochem Biophys Res Commun 420:762–767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Palam LR, Jiang L et al (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283:7064–7073

    Article  CAS  PubMed  Google Scholar 

  • Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225

    Article  CAS  PubMed  Google Scholar 

  • Zimmet JM, Hare JM (2006) Nitroso-redox interactions in the cardiovascular system. Circulation 114:1531–1544

    Article  PubMed  Google Scholar 

  • Zitka O, Skalickova S, Gumulec J et al (2012) Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett 4:1247–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported in part by the National Institutes of Health [R01 DA034185, R01 MH101183, R01 ES025549 to SDB, R01 MH101183 to MAK, and F32 MH116604 to EAB], and the Massachusetts General Hospital Executive Committee on Research Interim Support Funding to MAK.

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Bordt, E.A., Smith, C.J., Demarest, T.G. et al. Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response. Neurotox Res 36, 239–256 (2019). https://doi.org/10.1007/s12640-018-9962-7

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